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Cynthia Yu-Wai-Man, Richard M H Lee, Scott Larsen, Richard Neubig, Peng Tee Khaw; Novel MRTF/SRF inhibitors prevent conjunctival scarring after glaucoma filtration surgery: An ex vivo and in vivo study. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2927.
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© ARVO (1962-2015); The Authors (2016-present)
Post-surgical scarring remains the main cause of failure of glaucoma filtration surgery and current antimetabolites carry the risk of potentially blinding complications. There is increasing evidence that the Myocardin-related transcription factor/Serum response factor (MRTF/SRF) pathway plays a pivotal role in myofibroblast activation. We thus hypothesised that inhibiting the MRTF/SRF pathway would reduce scarring in an aggressive rabbit model of conjunctival fibrosis.
Ex vivo segments of rabbit conjunctiva were cultured in 100μM MRTF inhibitor 1 or PBS control and imaged for tissue area changes over 30 days. We validated our results using a randomised, prospective, masked-observer study of 24 New Zealand White female rabbits undergoing glaucoma filtration surgery. The animals received either intraoperative 0.2mg/ml mitomycin-C (MMC) [N=6] or postoperative subconjunctival injections of 100μM MRTF inhibitor 1 [N=6] or 100μM MRTF inhibitor 2 [N=6] or PBS [N=6]. Bleb morphology and intraocular pressure were recorded over 30 days. Tissue sections were immunohistochemically graded on day 30. We analysed our results using Kaplan-Meier curve Log-rank test and Student’s t-test.
Ex vivo conjunctival tissue contraction was significantly reduced by 35%(day 6), 39%(day 15), 48%(day 21) and 68%(day 30) with inhibitor 1 compared to PBS (Fig 1). In vivo, bleb survival was significantly improved with inhibitor 1 (p=0.01) and inhibitor 2 (p=0.0005) compared to PBS (Fig 2). The mean day of bleb failure was 28.8 (range=24-30) for MMC, 28.5 (range=24-30) for inhibitor 2, 24.5 (range=15-30) for inhibitor 1, and 14 (range=12-18) for PBS. IOP also remained significantly lower with inhibitor 1 (p=0.027) and inhibitor 2 (p=0.0005) compared to PBS. MMC treatment led to thin avascular blebs with destruction of the epithelial layer. MRTF inhibitors however were not toxic and significantly reduced conjunctival scarring using H&E, picrosirius red, Gomori’s trichrome, and alpha-smooth muscle actin staining (p<0.05).
Novel MRTF inhibitors significantly improved bleb survival and prevented conjunctival scarring. MRTF inhibitor 2 had more potent anti-scarring effects than inhibitor 1. They were safe for subconjunctival delivery and less destructive to local tissue than MMC. MRTF inhibitors show potential as a novel class of anti-fibrotic agents in glaucoma filtration surgery.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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